N4-acetylcytidine (ac4C) is a critical RNA modification implicated in cancer progression. Currently, N-acetyltransferase 10 (NAT10) is recognized as the sole "writer" protein responsible for ac4C modification. However, the study of NAT10 and ac4C modification in lung cancer remains sparse. In this study, we observed a significant upregulation of NAT10 expression in lung cancer, which is strongly correlated with poor prognostic outcomes. In vitro and in vivo experiments have demonstrated that NAT10 facilitates the proliferation, migration, and invasion of non-small cell lung cancer (NSCLC) cells while inhibiting autophagy flux. Mechanistically, NAT10 may enhance mRNA stability through ac4c modification at the 3' untranslated region (UTR) of SGK2 mRNA. Furthermore, SGK2 interacts with EZH2 and phosphorylates it at threonine 367, leading to increased protein stability of EZH2 and a reduction in its ubiquitination. Additionally, NAT10 impedes autophagy flux by preventing the fusion of autophagosomes with lysosomes and suppressing GABARAP transcription, which is regulated by EZH2-mediated H3K27me3. In summary, our study elucidates the biological significance and molecular mechanisms of the NAT10/SGK2/EZH2 axis in the pathogenesis of lung cancer, potentially providing novel prognostic markers and therapeutic targets for its treatment.